This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g. as a result of increased expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.
Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer""s disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis; allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
In one particular embodiment, the present invention relates to protease inhibitors of Formula I: 
in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;
n is 0, 1, 2 or 3;
X1 is xe2x95x90Cxe2x80x94 or xe2x80x94CHxe2x80x94;
X2 is a bond or a divalent group of Formula (a) or (b): 
xe2x80x83wherein:
X3 and X4 independently are xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2S(O)2xe2x80x94
R9 and R10 independently are hydrogen, (C1-6)alkyl or as defined below;
R11 at each occurrence independently is hydrogen or (C1-6)alkyl;
R12 and R13 independently are (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)R16, xe2x80x94S(O)2R16, xe2x80x94C(O)R16, xe2x80x94C(O)OR16, xe2x80x94OC(O)R16, xe2x80x94NR16R17, xe2x80x94NR17C(O)R16, xe2x80x94NR17C(O)OR16, xe2x80x94C(O)NR16R17, xe2x80x94S(O)2NR16R17, xe2x80x94NR17C(O)NR16R17 or xe2x80x94NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, halo, (C1-6)alkyl or R16 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R17 is hydrogen or (C1-6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR18R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C1-6)alkylene, R18 is hydrogen or (C1-6)alkyl and R19 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR18R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, oxo, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X55NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R1 is xe2x80x94X6X7R20, wherein X6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X7 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR21xe2x80x94, wherein R21 is hydrogen or (C1-6)alkyl, and R20 is (i) (C1-6)alkyl optionally substituted by cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR22, xe2x80x94SR22, xe2x80x94S(O)R22, xe2x80x94S(O)2R22, xe2x80x94C(O)R22, xe2x80x94C(O)OR22, xe2x80x94C(O)NR22R23, xe2x80x94NR22R23, xe2x80x94NR23C(O)R22, xe2x80x94NR23C(O)OR22, xe2x80x94NR23C(O)NR22R23 or xe2x80x94NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8-12)bicycloaryl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8-12)bicycloaryl(C0-6)alkyl or (iii) (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by xe2x80x94R24, xe2x80x94X5OR24, xe2x80x94X5SR24, xe2x80x94X5S(O)R24, xe2x80x94X5S(O)2R24, xe2x80x94X5C(O)R24, xe2x80x94X5C(O)OR24 xe2x80x94X5C(O)NR24R25, xe2x80x94X5NR24R25, xe2x80x94X5NR25C(O)R24, xe2x80x94X5NR25C(O)OR24, xe2x80x94X5NR25C(O)NR24R25 or xe2x80x94X5NR25C(NR25)NR24R25, wherein X5 is as defined above, R24 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl and R25 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl;
R2 is hydrogen or (C1-6)alkyl;
R3 is (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94SR26, xe2x80x94C(O)OR26, xe2x80x94C(O)NR26R26, xe2x80x94P(O)(OR26)OR26, xe2x80x94OP(O)(OR26)OR26, xe2x80x94S(O)R27, xe2x80x94S(O)2R27 or xe2x80x94C(O)R27, wherein R26 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R27 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, or (ii) (C5-6)cycloalkyl(C2-3)alkyl, hetero(C3-6)cycloalkyl(C2-3)alkyl, (C6-12)aryl(C2-3)alkyl or hetero(C5-6)aryl(C2-3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C1-5)alkyl and R4 is hydrogen or unsubstituted (C1-5)alkyl, then X2 may not represent (i) a bond when R1 is xe2x80x94C(O)R20, xe2x80x94C(O)2R20 or xe2x80x94S(O)2R20 in which R20 is (C1-6)alkyl, phenyl(C1-4)alkyl, phenyl, (C3-7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C1-4)alkyl, perfluoro(C1-4)alkyl, (C1-4)alkoxy, hydroxy, halo, amido, nitro, amino, (C1-4)alkylamino, (C1-4)dialkylamino, carboxy or (C1-4)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C1-4)alkyl, perfluoro(C1-4)alkyl, (C1-4)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C1-4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C1-6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7is a group selected from cyano, halo, nitro, xe2x80x94R29, xe2x80x94X5NR29R30, xe2x80x94X5NR30C(O)OR29, xe2x80x94X5NR30C(O)NR29R30, xe2x80x94X5NR30C(NR30)NR29R30, xe2x80x94X5OR29, xe2x80x94X5SR29, xe2x80x94X5C(O)OR29, xe2x80x94X5C(O)NR29R30, xe2x80x94X5S(O)2NR29R30, xe2x80x94X5P(O)(OR30)OR29, xe2x80x94X5OP(O)(OR29)OR29, xe2x80x94X5NR30C(O)R31, xe2x80x94X5S(O)R31, xe2x80x94X5S(O)2R31 and xe2x80x94X5C(O)R31, wherein X5 is as defined above, R29 is hydrogen or xe2x80x94R31, R30 at each occurrence is hydrogen or (C1-6)alkyl and R31 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof; but excluding compounds selected from the group consisting of ((S)-1-{(S)-1-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, {1-[1-(1-1H-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester, [(S)-3-methyl-1-((S)-3-methyl-1-{1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanoyl}-butylcarbamoyl)-butyl]-carbamic acid benzyl ester; {(S)-1-[(S)-1-(1-1H-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester, ((S)-1-{(S)-1-[1-(1-benzyl-1H-imidazol-2-yl)-methanoyl]-3-methyl-butylcarbamoyl}-3-methyl-butyl)-carbamic acid benzyl ester, {(S)-1-[(S)-1-(1-1H-imidazol-2-yl-methanoyl)-3-methyl-butylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester, 3-{[1-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-4-pyridin-3-yl-butyric acid ethyl ester, 4-furan-2-yl-4-oxo-3-{[1-(4-trifluoromethyl-phenyl)-methanoyl]-amino}-butyric acid ethyl ester, 3-(2-methyl-propanoylamino)-4-oxo-4-thiophen-2-yl-butyric acid ethyl ester, 4-oxo-4-thiophen-2-yl-3-[(1-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 4-(5-bromo-thiophen-2-yl)-3-{[1-(4-chloro-phenyl)-methanoyl]-amino}-4-oxo-butyric acid ethyl ester, 3-{[1-(4-chloro-phenyl)-methanoyl]-amino}-4-(5-methyl-thiophen-2-yl)-4-oxo-butyric acid ethyl ester, 4-oxo-4-thiophen-3-yl-3-[(1-p-tolyl-methanoyl)-amino]-butyric acid ethyl ester, 3-{[1-(4-methoxy-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 3-{[1-(3,4-dichloro-phenyl)-methanoyl]-amino}-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester, 4-fluoro-N-[1-(1-thiophen-3-yl-methanoyl)-propyl]-benzamide, 4-{[1-(4-fluoro-phenyl)-methanoyl]-amino}-5-oxo-5-thiophen-3-yl-pentanoic acid ethyl ester and 3-{[1-(4-fluoro-phenyl)-methanoyl]-amino}-2-methyl-4-oxo-4-thiophen-3-yl-butyric acid ethyl ester.
In another particular embodiment, the present invention relates to protease inhibitors of Formula I: 
in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;
n is 0, 1, 2 or 3;
X1 is xe2x95x90Cxe2x80x94 or xe2x80x94CHxe2x80x94;
X2 is a bond or a divalent group of Formula (a) or (b): 
xe2x80x83wherein:
X3 and X4 independently are xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2S(O)2xe2x80x94;
R9 and R10 independently are hydrogen, (C1-6)alkyl or as defined below;
R11 at each occurrence independently is hydrogen or (C1-6)alkyl;
R12 and R13 independently are (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)R16, xe2x80x94S(O)2R16, xe2x80x94C(O)R16, xe2x80x94C(O)OR16, xe2x80x94OC(O)R16, xe2x80x94NR16R17, xe2x80x94NR17C(O)R16, xe2x80x94NR17C(O)OR16, xe2x80x94C(O)NR16R17, xe2x80x94S(O)2NR16R17, xe2x80x94NR17C(O)NR16R17 or xe2x80x94NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R15 (C1-6)alkyl or halo-substituted (C1-3)alkyl, R16 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R17 is hydrogen or (C1-6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR18R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5 is a bond or (C1-6)alkylene, R18 is hydrogen or (C1-6)alkyl and R19 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR18R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; or
R12 together with R9 and/or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, oxo, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are defined above; and
R1 is xe2x80x94X6X7R20, wherein X6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X7 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR21xe2x80x94, wherein R21 is hydrogen or (C1-6)alkyl, and R20 is (i) (C1-6)alkyl optionally substituted by cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR22, xe2x80x94SR22, xe2x80x94S(O)R22, xe2x80x94S(O)2R22, xe2x80x94C(O)R22, xe2x80x94C(O)OR22, xe2x80x94C(O)NR22R23, xe2x80x94NR22R23, xe2x80x94NR23C(O)R22, xe2x80x94NR23C(O)OR22, xe2x80x94NR23C(O)NR22R23 or xe2x80x94NR23C(NR23)NR22R23, wherein R14 and R15 are as defined above, R22 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8 12)bicycloaryl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, dihetero(C5-6)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8-12)bicycloaryl(C0-6)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substituted by xe2x80x94R24, xe2x80x94X5OR24, xe2x80x94X5SR24, xe2x80x94X5S(O)R24, xe2x80x94X5S(O)2R24, xe2x80x94X5C(O)R24, xe2x80x94X5C(O)OR24, xe2x80x94X5C(O)NR24R25, xe2x80x94X5NR24R25, xe2x80x94X5NR25C(O)R24, xe2x80x94X5NR25C(O)OR24, xe2x80x94X5NR25C(O)NR24R25 or xe2x80x94X5NR25C(NR25)NR24R25, wherein X5 is as defined above, R24 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8-12)bicycloaryl(C0-6)alkyl and R25 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; or when X2 is a divalent group of formula (a) or (b) then R1 may also represent hydrogen, carboxy, oxalo or carbamoyl;
R2 is hydrogen or (C1-6)alkyl;
R3 is (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94SR24, xe2x80x94C(O)OR24, xe2x80x94C(O)NR24R24, xe2x80x94P(O)(OR24)OR24, xe2x80x94OP(O)(OR24)OR24, S(O)R25, S(O)2R25 or xe2x80x94C(O)R25, wherein R24 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R25 (C1-6)alkyl or halo-substituted (C1-3)alkyl, or (ii) (C5-6)cycloalkyl(C2-3)alkyl, hetero(C3-6)cycloalkyl(C2-3)alkyl, (C6-12)aryl(C2-3)alkyl or hetero(C5-6)aryl(C2-3)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally is substituted further with 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above, provided that when R3 is unsubstituted (C1-5)alkyl and R4 is hydrogen or unsubstituted (C1-5)alkyl, then X2 may not represent (i) a bond when R1 is xe2x80x94C(O)R20, xe2x80x94C(O)2R20 or xe2x80x94S(O)2R20 in which R20 is (C1-6)alkyl, phenyl(C1-4)alkyl, phenyl, (C3-7)cycloalkyl, camphan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C1-4)alkyl, perfluoro(C1-4)alkyl, (C1-4)alkoxy, hydroxy, halo, amido, nitro, amino, (C1-4)alkylamino, (C1-4)dialkylamino, carboxy or (C1-4)alkoxycarbonyl, or naphth-1-yl or naphth-2-yl substituted by one or more of (C1-4)alkyl, perfluoro(C1-4)alkyl, (C1-4)alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C1-4)alkoxycarbonyl or (ii) a divalent group of formula (a) or (b) in which the moiety R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or wherein R9 and R12 form ethylene, trimethylene, hydroxy-substituted trimethylene, tetramethylene or phenylene-1,2-dimethylene; or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R5, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R4is hydrogen, (C1-6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7is a group selected from cyano, halo, nitro, xe2x80x94R29, xe2x80x94X5NR29R30, xe2x80x94X5NR30C(O)OR29, xe2x80x94X5NR30C(O)NR29R30, xe2x80x94X5NR30C(NR30)NR29R30, xe2x80x94X5OR29, xe2x80x94X5SR29, xe2x80x94X5C(O)OR29, xe2x80x94X5C(O)NR29R30, xe2x80x94X5S(O)2NR29R30, xe2x80x94X5P(O)(OR30)OR29, xe2x80x94X5OP(O)(OR29)OR29, xe2x80x94X5NR30C(O)R20, xe2x80x94X5S(O)R20, xe2x80x94X5S(O)2R20, xe2x80x94X5C(O)R20 and xe2x80x94C(O)NR42CHR43C(O)OR29, wherein X5 and R20 are as defined as above, R29 is hydrogen or xe2x80x94R20, wherein R20 is defined as above, R30 at each occurrence is hydrogen or (C1-6)alkyl, R42 is hydrogen, (C1-6)alkyl or together with R43 forms trimethylene, tetramethylene or phenylene-1,2-dimetbylene, optionally substituted with hydroxy or oxo, and R43 is as defined above or is (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)R16, xe2x80x94S(O)2R16, C(O)R16, xe2x80x94C(O)OR16, xe2x80x94OC(O)R16, xe2x80x94NR16R17, xe2x80x94NR17C(O)R16, xe2x80x94NR17C(O)OR16, xe2x80x94C(O)NR16R17, xe2x80x94S(O)2NR16R17, xe2x80x94NR17C(O)NR16R17 or xe2x80x94NR17C(NR17)NR16R17 or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR18R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5, R14, R15, R16, R17, R18 and R19 are as defined above; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C1-6)alkyl, halo-substituted (C1-4)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 (C1-6)alkyl or halo-substituted (C1-3)alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
In another particular embodiment, the present invention relates to a compound of Formula II: 
in which:
A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom;
n is 0, 1, 2 or 3;
X1 is xe2x95x90Cxe2x80x94 or xe2x80x94CHxe2x80x94;
X8 is (C1-2)alkylene;
R1 is hydrogen, carboxy, oxalo, carbamoyl or xe2x80x94X6X7R20, wherein X6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X7 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR21xe2x80x94, wherein R21 is hydrogen or (C1-6)alkyl, and R20 is (i) (C1-6)alkyl optionally substituted by cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR22, xe2x80x94SR22, xe2x80x94S(O)R22, xe2x80x94S(O)2R22, xe2x80x94C(O)R22, xe2x80x94C(O)OR22, xe2x80x94C(O)NR22R23, xe2x80x94NR22R23, xe2x80x94NR23C(O)R22, xe2x80x94NR23C(O)OR22, xe2x80x94NR23C(O)NR22R23 or xe2x80x94NR23C(NR23)NR22R23, wherein R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, R22 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8-12)bicycloaryl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)bicycloaryl(C0-6)alkyl or hetero(C8-12)bicycloaryl(C0-6)alkyl or (ii) (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl substituted by xe2x80x94X5OR24, xe2x80x94X5SR24, xe2x80x94X5S(O)R24, xe2x80x94X5S(O)2R24, xe2x80x94X5C(O)R24, xe2x80x94X5C(O)OR24, xe2x80x94X5C(O)NR24R25, xe2x80x94X5NR24R25, xe2x80x94X5NR25C(O(R24, xe2x80x94X5NR25C(O)OR24, xe2x80x94X5NR25C(O)NR24R25 or xe2x80x94X5NR25C(NR25)NR24R25, wherein X5 is a bond or (C1-6)alkylene, R24 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl and R25 at each occurrence independently is hydrogen or (C1-6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R2 is hydrogen or (C1-6)alkyl;
R3 is (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94NR14R14, xe2x80x94NR14C(O)OR14, xe2x80x94NR14C(O)NR14R14, xe2x80x94NR14C(NR14)NR14R14, xe2x80x94OR14, xe2x80x94SR14, xe2x80x94C(O)OR14, xe2x80x94C(O)NR14R14, xe2x80x94S(O)2NR14R14, xe2x80x94P(O)(OR14)OR14, xe2x80x94OP(O)(OR14)OR14, xe2x80x94NR14C(O)R15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94OR16, xe2x80x94SR16, xe2x80x94S(O)R16, xe2x80x94S(O)2R16, xe2x80x94C(O)R16, xe2x80x94C(O)OR16, xe2x80x94OC(O)R16, xe2x80x94NR16R17, xe2x80x94NR17C(O)R16, xe2x80x94NR17C(O)OR16, xe2x80x94C(O)NR16R17, xe2x80x94S(O)2NR16R17, xe2x80x94NR17C(O)NR16R17 or xe2x80x94NR17C(NR17)NR16R17, wherein R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, R16 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R17 is hydrogen or (C1-6)alkyl, and wherein within R16 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR15R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5 is as defined above, R18 is hydrogen or (C1-6)alkyl and R19 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R18, xe2x80x94X5OR18, xe2x80x94X5SR18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18, xe2x80x94X5C(O)R18, xe2x80x94X5C(O)OR18, xe2x80x94X5OC(O)R18, xe2x80x94X5NR18R19, xe2x80x94X5NR19C(O)R18, xe2x80x94X5NR19C(O)OR18, xe2x80x94X5C(O)NR18R19, xe2x80x94X5S(O)2NR18R19, xe2x80x94X5NR19C(O)NR18R19 or xe2x80x94X5NR19C(NR19)NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and/or R13 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above, or
R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted with 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R4 is hydrogen, (C1-6)alkyl or as defined above;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7is a group selected from cyano, halo, nitro, xe2x80x94R29, xe2x80x94X5NR29R30, xe2x80x94X5NR30C(O)OR29, xe2x80x94X5NR30C(O)NR29R30, xe2x80x94X5NR30C(NR30)NR29R30, xe2x80x94X5OR29, xe2x80x94X5SR29, xe2x80x94X5C(O)OR29, xe2x80x94X5C(O)NR29R30, xe2x80x94X5S(O)2NR29R30, xe2x80x94X5P(O)(OR30)OR29, xe2x80x94X5OP(O)(OR29)OR29, xe2x80x94X5NR30C(O)R31, xe2x80x94X5S(O)R31, xe2x80x94X5S(O)2R31 and xe2x80x94X5C(O)R31, wherein X5 is as defined above, R29 is hydrogen or xe2x80x94R31, R30 at each occurrence is hydrogen or (C1-6)alkyl and R31 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl, wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; and
R8 at each occurrence independently is selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above;
R9 is hydrogen or (C1-6)alkyl; and
R32 is (C1-8)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein within R30 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94x5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5, R14 and R15 are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
In another particular embodiment, the present invention relates to a pharmaceutical composition which contains a compound of Formula I or II, or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers, or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
In another particular embodiment, the present invention relates to method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or II or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
In another particular embodiment, the present invention relates to processes for preparing compounds of Formula I and II and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof as set forth in xe2x80x9cDetailed Description of the Inventionxe2x80x9d.
In another particular embodiment, the present invention relates to protease inhibitors of Formula III: 
in which:
A comprises a heteromonocyclic radical containing 5 to 6 annular atoms or a fused heteropolycyclic radical containing 8 to 14 annular atoms, wherein each ring contains 5 to 7 annular atoms, X1 is an annular carbon atom and each annular atom other than X1 optionally is a heteroatom, with the proviso that when A is a heteromonocychc radical containing 5 annular atoms, no more than two of the annular atoms comprising the ring are heteroatoms;
X1 is selected from xe2x95x90Cxe2x80x94 and xe2x80x94CHxe2x80x94;
X2 is a bond or a divalent group of Formula (a) or (b): 
xe2x80x83wherein:
X3 and X5 independently are xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94,
X4 is xe2x80x94CHR11xe2x80x94, xe2x80x94CH2CHR11xe2x80x94 or xe2x80x94CHR11CH2xe2x80x94 and X6 is xe2x80x94CHR12xe2x80x94, xe2x80x94CH2CHR12xe2x80x94 or xe2x80x94CHR12CH2xe2x80x94 wherein:
R11 and R12 are independently (i) (C1-6)alkyl or halo-substituted(C1-6)alkyl optionally substituted with xe2x80x94OR13, xe2x80x94SR13, xe2x80x94S(O)R13, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94NR13R14, xe2x80x94NR14C(O)OR13, xe2x80x94C(O)NR13R14, S(O)2NR13R14, xe2x80x94NR14C(O)NR13R14 or xe2x80x94NR14C(NR14)NR13R14, wherein R13 is hydrogen, (C1-6)alkyl, (C3-12)cycloalkyl(C0-5)alkyl, hetero(C3-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl or hetero(C5-12)aryl(C0-3)alkyl and R14 is hydrogen or (C1-4)alkyl, or (ii) (C3-12)cycloalkyl(C0-3)alkyl, hetero(C3-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)polycycloaryl(C0-3)alkyl or hetero(C8-12)polycycloaryl(C0-3)alkyl optionally substituted with xe2x80x94R15, xe2x80x94X7OR15, xe2x80x94X7SR15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94C(O)OR15, xe2x80x94X7NR15R16, xe2x80x94X7NR16C(O)OR15, xe2x80x94C(O)NR15R16, xe2x80x94S(O)2NR15R16, xe2x80x94NR16C(O)NR15R16 or xe2x80x94NR16C(NR16)NR15R16, wherein X7 is a bond or methylene, R15 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C3-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(CO0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)polycycloaryl(C0-3)alkyl or hetero(C8-12)polycycloaryl(C0-3)alkyl and R16 is hydrogen or (C1-6)alkyl, or (iii) together with R9 or R10, respectively, when X4 is xe2x80x94CHR11xe2x80x94 and/or X6 is xe2x80x94CHR12xe2x80x94, forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R11 and/or R12 are optionally independently substituted with halo, nitro, cyano, (C1-6)alkyl, halo-substituted(C1-6)alkyl, xe2x80x94OR17, xe2x80x94C(O)R17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR17R17, xe2x80x94S(O)2NR17R17, xe2x80x94X7NR17R17, xe2x80x94X7NR17C(O)OR17, xe2x80x94X7NR17C(O)NR17R17 or xe2x80x94X7NR17C(NR17)NR17R17, wherein X7 is as defined above and each R17 independently is hydrogen or (C1-6)alkyl; and
R9 and R10 are independently hydrogen, (C1-6)alkyl or as defined above;
R1 is hydrogen or xe2x80x94X8X9R18, wherein X8 is xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X9 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR19xe2x80x94, wherein R19 is hydrogen or (C1-6)alkyl, and R18 is (i) (C1-6)alkyl or halo-substituted(C1-6)alkyl optionally substituted with xe2x80x94OR13, xe2x80x94SR13, xe2x80x94S(O)R13, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94NR13R14, xe2x80x94NR14C(O)OR13, xe2x80x94C(O)NR13R14, xe2x80x94S(O)2NR13R14, xe2x80x94NR14C(O)NR13R14 or xe2x80x94NR14C(NR14)NR13R14, wherein R13 and R14 are as defined above, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, dihetero(C5-6)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl optionally substituted with xe2x80x94R15, xe2x80x94X7OR15, xe2x80x94X7SR15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94C(O)OR15, xe2x80x94X7NR15R16, xe2x80x94X7NR16C(O)OR15, xe2x80x94C(O)NR15R16, xe2x80x94S(O)2NR15R16, xe2x80x94NR16C(O)NR15R16 or xe2x80x94NR16C(NR16)NR15R16, wherein X7, R15 and R16 are as defined above; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R1 optionally independently are substituted with halo, nitro, cyano, (C1-6)alkyl, halo-substituted(C1-6)alkyl, xe2x80x94OR17, xe2x80x94C(O)R17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR17R17, xe2x80x94S(O)2NR17R17, xe2x80x94X7NR17R17, xe2x80x94X7NR17C(O)OR17, xe2x80x94X7NR17C(O)NR17R17 or xe2x80x94X7NR17C(NR17)NR17R17, wherein X7 R17 are as defined above;
R2 is hydrogen or (C1-6)alkyl;
R3 is phenyl(C2-3)alkyl, hetero(C5-6)aryl(C2-3)alkyl, (C5-6)cycloalkyl(C2-3)alkyl or hetero(C5-6)cycloalkyl(C2-3)alkyl, wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R3 optionally independently are substituted with halo, nitro, cyano, (C1-6)alkyl, halo-substituted(C1-6)alkyl, xe2x80x94OR17, xe2x80x94C(O)R17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR17R17, xe2x80x94S(O)2NR17R17, xe2x80x94X7NR17R17, xe2x80x94X7NR17C(O)OR17, xe2x80x94X7NR17C(O)NR17R17 xe2x80x94X7NR17C(NR17)NR17R17, wherein X7 and R17 are as defined above, and R4 is hydrogen or R3 and R4 are both methyl, ethyl or propyl or together with the carbon atom to which both R3 and R4 are attached form cyclopropylene, cyclobutylene or cyclopentylene;
R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo;
R7is halo, nitro, xe2x80x94R20, xe2x80x94OR20, xe2x80x94C(O)R20, xe2x80x94C(O)OR20, xe2x80x94S(O)2NR20OR21, xe2x80x94C(O)NR20R21 or xe2x80x94C(O)NR22CHR23C(O)OR20 and bonded to any annular carbon atom with a free valence comprising A, wherein:
R20 is hydrogen or R18, wherein R18 is as defined above;
R21 is hydrogen or (C1-6)alkyl;
R22 is hydrogen, (C1-6)alkyl or together with R23 forms trimethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; and
R23 is as defined above or is (i) (C1-6)alkyl or halo-substituted(C1-6)alkyl optionally substituted with xe2x80x94OR13, xe2x80x94SR13, xe2x80x94S(O)R13, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94NR13R14, xe2x80x94NR14C(O)OR13, xe2x80x94C(O)NR13R14, xe2x80x94S(O)2NR13R14, xe2x80x94NR14C(O)NR13R14 or xe2x80x94NR14C(NR14)NR13R14, wherein R13 and R14 are as defined above, or (ii) (C3-10)cycloalkyl(C0-3)alkyl, hetero(C3-10)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)polycycloaryl(C0-3)alkyl or hetero(C8-12)polycycloaryl(C0-3)alkyl optionally substituted with xe2x80x94R15, xe2x80x94X7OR15, xe2x80x94X7SR15, xe2x80x94S(O)R15, xe2x80x94S(O)2R15, xe2x80x94C(O)R15, xe2x80x94C(O)OR15, xe2x80x94X7NR15R16, xe2x80x94X7NR16C(O)OR15, xe2x80x94C(O)NR15R16, xe2x80x94S(O)2NR15R16, xe2x80x94NR16C(O)NR15R16 or xe2x80x94NR16C(NR16)NR15R16, wherein X7, R15 and R16 are as defined above; wherein any 1 to 3 annular atoms of any aromatic ring with available valences comprising R20 and/or R21 optionally independently are substituted with halo, nitro, cyano, (C1-6)alkyl, halo-substituted(C1-6)alkyl, xe2x80x94OR17, xe2x80x94C(O)R17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR17R17, xe2x80x94S(O)2NR17R17, xe2x80x94X7NR17R17, xe2x80x94X7NR17C(O)OR17, xe2x80x94X7NR17C(O)NR17R17 or xe2x80x94X7NR17C(NR17)NR17R17, wherein X7 and R17 are as defined above; and
R8 is hydrogen, halo, hydroxy, formyl, carboxy, carbamoyl, sulfamoyl or (C1-6)alkyl and bonded to any annular carbon atom with a free valence comprising A; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
Definitions
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the meanings given this Section:
xe2x80x9cAlicyclicxe2x80x9d means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAliphaticxe2x80x9d means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAlkenylxe2x80x9d means alkyl, as defined in this Application, provided that the radical is comprised of at least one double bond. Hence, optionally substituted (C2-6)alkenyl as used in this Application to define R32 includes 2-bromovinyl (xe2x80x94CHxe2x95x90CHBr), buta-1,3-dienyl (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH2), 2-chloro-1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CClxe2x80x94CH3), 2-chlorovinyl (xe2x80x94CHxe2x95x90CHCl), 4-isopropenyl (xe2x80x94C(CH3)xe2x95x90CH2), 1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH3), 2-methylpropenyl (xe2x80x94CHxe2x95x90C(CH3)2), 2-nitrovinyl (xe2x80x94CHxe2x95x90CHNO2), propenyl (xe2x80x94CHxe2x95x90CHxe2x80x94CH3), 2-trifluoromethylvinyl (xe2x80x94CHxe2x95x90CHxe2x80x94CF3), trifluorovinyl (xe2x80x94CFxe2x95x90CF2), vinyl (xe2x80x94CHxe2x95x90CH2), and the like).
xe2x80x9cAlkoxyxe2x80x9d means the radical xe2x80x94OR, wherein R is alkyl as defined in this Application, having the number of carbon atoms indicated (e.g., (C1-4)alkoxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
xe2x80x9cAlkylxe2x80x9d represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g. (C1-6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g. as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g. (C6-12)aryl(C0-6)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
xe2x80x9cAlkylenexe2x80x9d, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylene includes methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), trimethylene (xe2x80x94CH2CH2CH2xe2x80x94), 2-methyltrimethylene (xe2x80x94CH2CH(CH3)CH2xe2x80x94), tetramethylene (xe2x80x94CH2CH2CH2CH2xe2x80x94), 2-butenylene (xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94), 2-methyltetramethylene (xe2x80x94CH2CH(CH3)CH2CH2xe2x80x94), pentamethylene (xe2x80x94CH2CH2CH2CH2CH2xe2x80x94) and the like). For example, a group of Formula (a), wherein R11 is hydrogen and R12 taken together with R9 forms optionally substituted trimethylene is depicted by the following illustration: 
in which R is an optional hydroxy or oxo group and X3 and R1 are as defined in the Summary of the Invention for Formulae I and II.
xe2x80x9cAlkylidenexe2x80x9d means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylidene includes methylene (xe2x95x90CH2), ethylidene (xe2x95x90CHCH3), isopropylidene (xe2x95x90C(CH3)2), propylidene (xe2x95x90CHCH2CH3), allylidene (xe2x95x90CHCHxe2x95x90CH2), and the like).
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cAnimalxe2x80x9d includes humans, non-human mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, or the like) and non-mammals (e.g. birds, or the like).
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly. For example,(C6-12)aryl as used in this Application to define R1 includes phenyl, naphthyl and biphenylyl.
xe2x80x9cAromaticxe2x80x9d means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. For example, a compound of Formula I wherein R7 contains a carboxy moiety may exist as either the unprotected or a protected derivative, e.g. wherein R7 is methoxycarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCycloalkylxe2x80x9d means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of ring member carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C3-12)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like).
xe2x80x9cCycloalkylenexe2x80x9d means a saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, the instance wherein R3 and R4 together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following: 
in which R2, R5 and R6 are as defined in the Summary of the Invention, and any substituted derivative thereof.
xe2x80x9cDiseasexe2x80x9d specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the xe2x80x9cside effectsxe2x80x9d of such therapy.
xe2x80x9cFused heteropolycyclic ring systemxe2x80x9d means a saturated, partially saturated or aromatic moiety containing two or more rings, wherein at least two ring member atoms of one ring are common to a second ring containing the number of ring member atoms indicated in which at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivative thereof. For example, the term xe2x80x9ca fused heteropolycyclic radical containing 8 to 14 ring member atomsxe2x80x9d as used in this Application to define A may include acridinyl, benzofuryl, benzooxazolyl, benzothiazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, indazolyl, indolinyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isochromanyl, isoindolinyl, isoquinolyl, naphthyridinyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolizinyl, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl, quinuclidinyl, xanthenyl, and the like.
xe2x80x9cGuanidinoxe2x80x9d means the radical xe2x80x94NHC(NH)NH2. Unless indicated otherwise, the compounds of the invention containing guanidino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo.
xe2x80x9cHalo-substituted alkylxe2x80x9d, as a group or part of a group, means xe2x80x9calkylxe2x80x9d substituted by one or more xe2x80x9chaloxe2x80x9d atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1-3)alkyl includes chloromethyl, dicloromethyl, difluoromethyl, trifluromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
xe2x80x9cHeteroarylxe2x80x9d means aryl, as defined herein, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 ring member atoms. For example, hetero(C5-12)aryl as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2,4xe2x80x2]bipyridinylyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl, pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl, tetrazolyl, thiazolyl, 4-thiazol-4-ylphenyl, thienyl, xanthenyl, and the like.
xe2x80x9cHeteroatom moietyxe2x80x9d includes xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group.
xe2x80x9cHeterocycloalkylxe2x80x9d means cycloalkyl, as defined herein, provided that one or more of the ring member carbon atoms indicated is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. the term hetero(C5-12)cycloalkyl includes [1,4xe2x80x2]bipiperidinylyl, dihydrooxazolyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R1 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g. wherein R1 is 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHeterocycloalkylenexe2x80x9d means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen or (C1-6)alkyl. For example, the instance wherein R3 and R4 together with the carbon atom to which both R3 and R4 are attached form hetero(C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following: 
in which R is hydrogen, (C1-6)alkyl or a protecting group and R2 is as defined in the Summary of the Invention, and any substituted derivative thereof.
xe2x80x9cHeteromonocyclicxe2x80x9d means a saturated, partially saturated or aromatic monocyclic radical containing the number of ring member atoms indicated in which at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivative thereof. For example, the term xe2x80x9ca heteromonocyclic containing 5 to 6 ring member atomsxe2x80x9d as used in this Application to define A may include dihydrooxazolyl, furazanyl, furyl, imidazolyl, imidazolidinyl, imidazolinyl, isooxazolyl, isothiazolyl, thiazolyl, thienyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pirazolidinyl, pirazolinyl, pyranyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrazolyl, and the like.
xe2x80x9cHeteropolycycloarylxe2x80x9d means polycycloaryl, as defined herein, except one or more of the ring member carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, hetero(C8-12)polycycloaryl includes 1xe2x80x2,2xe2x80x2-dihydro-2H-[1,4xe2x80x2]bipyridinylyl, chromanyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, and the like.
xe2x80x9cHydroxyxe2x80x9d means the radical xe2x80x94OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cIminoketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(NR)xe2x80x94, wherein R is hydrogen or (C1-6)alkyl.
xe2x80x9cIsomersxe2x80x9d mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes xe2x80x9coptical isomersxe2x80x9d. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g. see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, March, Jerry, John Wiley and Sons, New York, 1985). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.
xe2x80x9cKetone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cNitroxe2x80x9d means the radical xe2x80x94NO2.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9c(C1-6)alkyl optionally substituted with cyano, halo, nitro,xe2x80x9d means that the alkyl group referred to may or may not be substituted in order to fall within the scope of the invention.
xe2x80x9cOxaloxe2x80x9d means the radical xe2x80x94C(O)C(O)OH.
xe2x80x9cN-oxide derivativesxe2x80x9d means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., Oxe2x80x94N) and which possess the desired pharmacological activity.
xe2x80x9cOxoxe2x80x9d means the radical=O.
xe2x80x9cPathologyxe2x80x9d of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutaric acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
xe2x80x9cPhenylene-1,2-dimethylenexe2x80x9d means the divalent radical xe2x80x94CH2C6H4CH2xe2x80x94, wherein the methylene moieties are attached at the 1- and 2-positions of the phenylene moiety. For example, a group of Formula (a) in which R12 together with R9 forms optionally substituted phenylene-1,2-dimethylene is illustrated by the following formula: 
in which R is an optional hydroxy group and X3 and R1 are as defined in the Summary of the Invention for Formulae I and II.
xe2x80x9cPolycycloarylxe2x80x9d means a bicyclic ring assembly (directly linked by a single bond or fused) containing the number of ring member carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C9-12)polycycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthalenyl, and the like).
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I). For example an ester of a compound of Formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds of Formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters of compounds of Formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates. A prodrug derivative of a compound of Formula I wherein R5 and R6 together are oxo is depicted by the following formula: 
in which X13 is a bond, straight, saturated ethylene or (xe2x80x94CH2CR41R42CH2xe2x80x94), wherein R41 and R42 independently are hydrogen, halo or (C1-3)alkyl or taken together form methylene.
xe2x80x9cProtected derivativesxe2x80x9d means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors. For example, the compound of Formula I which is 2S-amino-N-(2-benzooxazol-2-yl-2-hydroxy-1S-phenethylethyl)-3-cyclohexylpropionamide (i.e., Compound 55, described in Example 6, infra) may be protected with a suitable amino protecting group, e.g. 9H-fluoren-9-ylmethoxycarbonyl, or a suitable hydroxy protecting group, e.g. tert-butyldimethylsilanyl, to provide, respectively, 9H-fluoren-9-ylmethyl 1S-(2-benzooxazol-2-yl-2-hydroxy-1S-phenethylethylcarbamoyl)-2-cyclohexylethylcarbamate (i.e., Compound 51, described in Example 4, infra) and 2S-amino-N-[2-benzooxazol-2-yl-2-(tert-butyldimethylsilanyloxy)-1S-phenethylethyl]-3-cyclohexylpropionamide (i.e., Compound 56, described in Example 7, infra). A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
xe2x80x9cRing memberxe2x80x9d, as in fused heteropolycyclic ring system containing 8 to 14 ring member atoms, means that the atoms referred to are ring members of the fused heteropolycyclic radical, but not taking into account ring members of any substituents present. Thus, for example, a heteropolycyclic radical containing 8 ring member atoms includes benzooxaxol-2-yl, benzofur-2-yl, 1H-indol-5-yl, benzothiazol-2-yl, and the like.
xe2x80x9cSulfamoylxe2x80x9d means the radical xe2x80x94S(O)2NH2. Unless indicated otherwise, the compounds of the invention containing sulfamoyl radicals include protected derivatives thereof. Suitable protecting groups for sulfamoyl radicals include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
xe2x80x9cThioketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(S)xe2x80x94.
xe2x80x9cTreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
While the broadest definition of the invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. A preferred aspect of the invention are compounds of Formula I in which X1 is xe2x95x90Cxe2x80x94. In particular, the heteromonocyclic ring or fused heteropolycyclic ring system A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is hydrogen, halo, (C1-4)alkoxy, (C1-4)alkoxycarbonyl, nitro or phenyl and R8 at each occurrence independently is halo, (C1-4)alkoxy, (C1-4)alkoxycarbonyl, nitro or trifluoromethyl. The ring system A preferably is benzoxazol-2-yl substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is hydrogen, halo, (C1-4)alkoxy, (C1-4)alkoxycarbonyl or nitro and R8 at each occurrence independently is halo, (C1-4)alkoxy, (C1-4)alkoxycarbonyl, nitro or trifluoromethyl.
X2 particularly represents a bond or a divalent group of Formula (a); particularly, wherein within Formula (a) X3 is xe2x80x94C(O)xe2x80x94, R9 represents hydrogen, R11 represents hydrogen or methyl, typically hydrogen, and R12 particularly represents (i) (C1-6)alkyl substituted with xe2x80x94SR14, xe2x80x94S(O)R14 or xe2x80x94S(O)2R14, wherein R14 is (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl or (ii) (C3-12)cycloalkyl(C0-6)alkyl or (C6-12)aryl(C0-6)alkyl; wherein within R12 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, -X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-4)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-6)alkyl or halo-substituted (C13)alkyl.
Further preferred, within Formula (a), R12 particularly represents a group having the following formula: 
in which q is 0, 1, 2, 4 or 5 and R33 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5C(O)OR14, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which q is 0, 1 or 2 and R33 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94OR14, xe2x80x94SR14 and xe2x80x94C(O)OR14, wherein R14 independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which R33 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl.
Further preferred, within Formula (a), R12 particularly represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl.
R1 particularly represents xe2x80x94X6X7R20, wherein X6 is xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X7 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR21xe2x80x94, wherein R21 is hydrogen or (C1-6)alkyl, and R20 is (i) (C1-6)alkyl optionally substituted by xe2x80x94C(O)OR14 or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl or (iii) (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl ring is substituted by xe2x80x94X5OR24, xe2x80x94X5C(O)R24, xe2x80x94X5C(O)OR24, xe2x80x94X5C(O)NR24R25, xe2x80x94X5NR24R25, xe2x80x94X5NR25C(O)R24, xe2x80x94X5NR25C(O)OR24, xe2x80x94X5NR25C(O)NR24R25 or xe2x80x94X5NR25C(NR25)NR24R25, wherein X5 is a bond or (C1-6)alkylene, R24 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl and R25 is hydrogen or (C1-6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 substituents independently selected from (C1-6)alkyl, halo, halo-substituted (C1-4)alkyl, xe2x80x94OR14 and xe2x80x94C(O)OR14 wherein R14 is hydrogen or (C1-6)alkyl, or when X2 is a divalent group of formula (a) then R1 may be, but is not limited to, hydrogen or oxalo.
R1 preferably is a group selected from acetyl, azetidin-3-ylcarbonyl, benzyloxycarbonyl, 1-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, bicyclo[2.2.1]hept-2-ylcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexylmethoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di(2-methoxyethyl)carbamoyl, dimethylcarbamoyl, 6-hydroxypyrid-3-ylcarbonyl, 1H-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, 2-morpholin-4-ylethylcarbonyl, naphth-1-ylacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydropyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl.
R1 especially represents morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl.
R2 typically is hydrogen.
R3 particularly represents hydrogen, (C1-6)alkyl (optionally substituted with cyano, halo, nitro, xe2x80x94SR26, xe2x80x94C(O)OR26, xe2x80x94C(O)NR26R26, xe2x80x94P(O)(OR26)OR26, xe2x80x94OP(O)(OR26)OR26, xe2x80x94S(O)R27, xe2x80x94S(O)2R27 or xe2x80x94C(O)R27, wherein R26 at each occurrence independently is hydrogen, (C1-6)alkyl, or halo-substituted (C1-3)alkyl and R27 is (C1-6)alkyl or halo-substituted (C1-3)alkyl) or (C6-12)aryl(C2-3)alkyl, wherein said aryl optionally is substituted further with 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)NR14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-6)cycloalkylene. In particular, R3 may be selected from hydrogen, (C1-4)alkyl (e.g. methyl, ethyl, n-propyl, n-butyl), phenyl(C2-3)alkyl (e.g. phenethyl) or (C1-4)alkylsulfonyl(C2-4)alkyl (e.g. 2-methylsulfonylethyl) or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-6)cycloalkylene (e.g. cyclobutylene or cyclohexylene). R3 preferably is (C1-4)alkyl.
R4 particularly represents hydrogen or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-6)cycloalkylene (e.g. cyclobutylene or cyclohexylene).
R5 and R6 preferably together form oxo.
Compounds of Formula II are preferred in which:
n is 0;
X1 is xe2x95x90Cxe2x80x94 and the ring system A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is hydrogen, halo, (C1-4)alkoxy, (C1-4)alkoxycarbonyl, nitro or phenyl and R8 at each occurrence independently is (C1-4)alkoxy, (C1-4)alkoxycarbonyl, nitro or trifluoromethyl.
X8 methylene or ethylene;
R1, R3 and R4 are as defined above;
R5 and R6 together form oxo;
R9 is hydrogen; and
R32 is xe2x80x94X9R34, wherein X9 is methylene when X8 is methylene and X9 is a bond when X8 is ethylene, R34 is xe2x80x94CR35xe2x95x90CHR36 or xe2x80x94CR37xe2x95x90NR38, wherein R35 and R36 together with the atoms to which R35 and R36 are attached form (C2-6)alkenyl, (C5-12)cycloalkenyl, hetero(C5-12)cycloalkenyl, (C6-12)aryl, hetero(C6-12)aryl, (C9-12)bicycloaryl or hetero(C8-12)bicycloaryl and R37 and R38 together with the atoms to which R37 and R38 are attached form hetero(C5-12)cycloalkenyl, hetero(C6-12)aryl or hetero(C8-12)bicycloaryl, wherein within R34 said cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5NR14C(O)OR14, xe2x80x94X5NR14C(O)N14R14, xe2x80x94X5NR14C(NR14)NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)OR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5S(O)2NR14R14, xe2x80x94X5P(O)(OR14)OR14, xe2x80x94X5OP(O)(OR14)OR14, xe2x80x94X5NR14C(O)R15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl.
R34 particularly represents (C6-12)aryl or hetero(C5-12)aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5C(O)OR14, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-2)alkylene, R14 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-3)alkyl or halo-substituted (C1-3)alkyl. R34 more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl or thienyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5C(O)OR14, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X4 is a bond or (C1-2)alkylene, R14 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-3)alkyl or halo-substituted (C1-3)alkyl. R34 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 4-tert-butylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dimethylisooxazol4-yl, 3,5-dimethylphenyl, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 6-methylpyrid-2-yl, 3-methyl-2-fluorophenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, prop-2-en-1-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-3-yl, o-tolyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 3-trifluoromethylsulfanylphenyl , 4-trifluoromethylsulfanylphenyl, 2,3,4-trifluoro phenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,3,6-trifluorophenyl.
A preferred group of compounds of Formula II are those in which xe2x80x94X8S(O)2R32 represents a group having the following formula: 
in which q is 0, 1, 2, 4 or 5 and R33 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X5NR14R14, xe2x80x94X5OR14, xe2x80x94X5SR14, xe2x80x94X5C(O)NR14R14, xe2x80x94X5C(O)OR14, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15 and xe2x80x94X5C(O)R15, wherein X5 is a bond or (C1-2)alkylene, R14 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which q is 0, 1 or 2 and R33 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-subsituted (C1-4)alkyl, nitro, xe2x80x94OR14, xe2x80x94SR14 and xe2x80x94C(O)OR14, wherein R14 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which R33 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl. In particular, xe2x80x94X8S(O)2R32 represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisooxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Further preferred are compounds of Formula I selected from a group consisting of:
2S-acetylamino-N-(1S-benzooxazol-2-ylcarbonyl)-3-phenylpropyl)-3-cyclohexylpropionamide; and
N-[1S-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-cyclohexylethylisonicotinamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
Further preferred are compounds of Formula I selected from a group consisting of:
N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethyl]morpholine-4-carboxamide;
methyl
1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-benzylsulfonylethylcarbamate;
N-(1S-benzooxazol-2-ylcarbonylbutyl)-2R-methylsulfonylamino-3-benzylsulfonylpropionamide;
N-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2R-(3,3-dimethylureido)-3-(2-methoxybenzylsulfonyl)propionamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylbutylcarbamoyl)-2-(2-methoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-benzylsulfonylethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-chlorobenzylsulfonyl)ethyl]morpholine-4-carboxamide;
1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethylcarbamate;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxyamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(3,5-dimethylisoxazol-4-ylmethylsulfonylethyl]isonicotinamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-nitrobenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-pyridin-2-ylmethylsulfonylethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-o-tolylmethylsulfonylethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-trifluoromethylbenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethyl]nicotinamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethyl]pyrazine-2-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-chlorobenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyl]isonicotinamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonylpentylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]isonicotinamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl)-3-phenylpropylcarbamoyl)-2-benzylsulfonylethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(6-methylpyrid-2-ylmethylsulfonyl)ethyl]isonicotinamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-nitrobenzylsulfonyl)ethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-pyrid-2-ylmethylsulfonylethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-o-tolylmethylsulfonylethyl]morpholine-4-carboxamide;
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-trifluoromethylbenzylsulfonyl)ethyl]tetrahydropyran-4-carboxamide;
tetrahydropyran-4-yl 1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethylcarbamate; and
N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-cyanobenzylsulfonyl)ethyl]piperidine-4-carboxamide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
A preferred aspect of the invention are compounds of Formula I in which X1 is xe2x95x90Cxe2x80x94. In particular, the heteromonocyclic ring or fused heteropolycyclic ring system A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, 1H-indol-5-yl, pyrid-2-yl, pyrid-3-yl thiazol-2-yl, 1-methyl-1H-imidazol-2-yl, 1-benzyl-1H-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 1,1-dioxo-1H-1xcex6-benzo[b]thien-2-yl, quinol-3-yl, [1,3]dioxolan-2-yl, naphtho[2,3-d]oxazol-2-yl, naphtho[1,2-d]oxazol-2-yl and naphtho[2,1-d]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is halo, nitro, xe2x80x94R29, xe2x80x94OR29, xe2x80x94C(O)R20, xe2x80x94C(O)OR29, xe2x80x94S(O)2NR29R30, xe2x80x94C(O)NR29R30 or xe2x80x94C(O)NHCHR43C(O)OR29, wherein R20 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R29 is hydrogen or xe2x80x94R20, wherein R20 is defined as above, wherein said heterocycloalkyl may be substituted with (C6-12)aryl(C0-3)alkyl, R30 at each occurrence is hydrogen or (C1-6)alkyl and R43 is (C1-6)alkyl, and R8 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-4)alkyl; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X6NR14R14, xe2x80x94X6NR14C(O)OR14, xe2x80x94X6NR14C(O)NR14R14, xe2x80x94X6NR14C(NR14)NR14R14, xe2x80x94X6OR14, xe2x80x94X6SR14, xe2x80x94X6C(O)OR14, xe2x80x94X6C(O)NR14R14, xe2x80x94X6S(O)2NR14R14, xe2x80x94X6P(O)(OR14)OR14, xe2x80x94X6OP(O)(OR14)OR14, xe2x80x94X6NR14C(O)R15, xe2x80x94X6S(O)R15, xe2x80x94X6S(O)2R15 and xe2x80x94X6C(O)R15, wherein X6 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 (C1-6)alkyl or halo-substituted (C1-3)alkyl.
The ring system A preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho[2,3-d]oxazol-2-yl, naphtho[1,2-d]oxazol-2-yl or naphtho[2,1-d]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is halo, xe2x80x94R29, xe2x80x94C(O)R20, xe2x80x94C(O)OR29, xe2x80x94C(O)NR29R30 or xe2x80x94S(O)2NR29R30, wherein R20 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl.
The ring system A more preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho[1,2-d]oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly wherein R7 is adamantan-1-ylmethylcarbamoyl, benzyl, benzylcarbamoyl, benzyl(methyl)carbamoyl, 1-benzyloxycarbonyl-3-methylbutylcarbamoyl, 4-benzylpiperidin-1-carbonyl, tert-butyl, chloro, 2,3-dihydroindol-1-ylcarbonyl, 3,4-dihydro-1H-isoquinol-2-ylcarbonyl, 3,4-dihydro-1H-quinol-1-ylcarbonyl, diphenylmethylcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2-(1H-indol-3-yl)ethylcarbamoyl, methoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-1-ylmethylcarbonyl, nitro, phenyl, phenylcarbamoyl, 2-phenylcyclopropylcarbamoyl, 1-phenylethylcarbamoyl, sulfamoyl, trifluoromethyl, phenethylcarbamoyl, 3-phenylpropylcarbamoyl, piperid-1-ylcarbonyl, pyrid-2-ylmethylcarbamoyl, pyrid-3-ylmethylcarbamoyl, pyrid-4-ylmethylcarbamoyl or pyrrolidin-1-ylcarbonyl and R8 is methyl.
X2 particularly represents a bond or a divalent group of Formula (a), wherein within Formula (a) X3 is xe2x80x94C(O)xe2x80x94, R9 represents hydrogen, R11 represents hydrogen or methyl, typically hydrogen, and R12 particularly represents (C1-6)alkyl, preferably isobutyl, sec-butyl or isopropyl.
R1 particularly represents hydrogen or xe2x80x94X8X9R20, wherein X8 is xe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X9 is a bond or xe2x80x94Oxe2x80x94 and R20 is (C1-6)alkyl, (C3-12)cycloalkyl(C3-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl or hetero(C5-12)aryl(C0-6)alkyl; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, xe2x80x94C(O)OR14, xe2x80x94X6NR14R14 and xe2x80x94X6NR14C(O)OR14, wherein X6 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 (C1-6)alkyl or halo-substituted (C1-3)alkyl.
R1 particularly represents acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo[2.2.2]hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl, 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-1-ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-morpholin-4-ylpropionyl, naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl or pyrid-3-ylcarbonyl, wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 3 radicals independently selected from 3-aminomethyl and 3-tert-butoxycarbonylaminomethyl.
R2 particularly represents hydrogen.
R3 preferably represents (C1-6)alkyl or (C6-10)aryl(C1-3)alkyl, more preferably phenethyl, or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-6)cycloalkylene, more preferably cyclopropylene.
R4 preferably represents hydrogen or (C1-6)alkyl, preferably hydrogen or methyl or R3 and R4 or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-6)cycloalkylene, more preferably cyclopropylene.
R5 and R6 preferably together form oxo.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Pharmacology and Utility
The compounds of the invention are cysteine protease inhibitors, in particular the compounds of the invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. Furthermore, the compounds of the invention are useful in treating bone resorption disorders, e.g. osteoporosis.
The compounds of the invention are inhibitors of cathepsin S and, as such, are useful for treating diseases in which cathepsin S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis, allergic disorders, including, but not limited to, asthma, and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts.
Cathepsin S also is implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g. emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate.
Furthermore, the compounds of the invention are useful as intermediates in the preparation of other compounds of Formula I. For example, compounds of Formula I in which R5 is hydroxy can be used to prepare compounds of Formula I in which R5 and R6 taken together form oxo.
Nomenclature
The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is cyclohexylmethyl; R1 is acetyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure: 
is named 2S-acetylamino-N-(1-benzooxazol-2-ylcarbonyl-3-phenylpropyl)-3-cyclohexylpropionamide; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is benzylsulfonylmethyl; R1 is morpholin-4-ylcarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; R5 is hydrogen; and R6 is hydroxy; that is, a compound having the following structure: 
is named N-[1S-(2-benzooxazol-2-yl-2-hydroxy-1S-phenethylethylcarbamoyl)-2-benzylsulfonylethyl]-morpholine-4-carboxamide or morpholine-4-carboxylic acid {(R)-1-[(S)-1-(1-benzooxazol-2-yl-1-hydroxy-methyl)-3-phenyl-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-amide; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is cyclohexymethyl; R1 is carboxyacetyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure: 
is named N-[1S-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-cyclohexylethyl]malonamic acid or N-{(S)-1-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-3-phenyl-propylcarbamoyl]-2-cyclohexyl-ethyl}-malonamic acid; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is 2-nitrobenzylsulfonylmethyl; R1 is morpholin-2-ylcarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure: 
is named N-[1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-(2-nitrobenzylsulfonyl)ethyl]morpholine-4-carboxamide or morpholine-4-carboxylic acid [(R)-1-[(S)-1-(-benzooxazol-2-yl-methanoyl)-3-phenyl-propylcarbamoyl]-2-(2-nitrophenylmethanesulfonyl)-ethyl]-amide; and a compound of Formula I in which A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is benzylsulfonylmethyl; R1 is tetrahydropyran-4-yloxycarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound having the following structure: 
is named tetrahydropyran-4-yl 1R-(1S-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl)-2-benzylsulfonylethylcarbamate or {(R)-1-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-3-phenyl-propylcarbamoyl]-2-phenylmethanesulfonyl-ethyl}-carbamic acid tetrahydro-pyran-4-yl ester.
A compound of Formula I in which A is pyrid-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is benzyloxycarbonyl; R2, R4 and R5 each are hydrogen; R3 is phenethyl; and R6 is hydroxy; that is, a compound having the following structure: 
is named benzyl 1S-(1S-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl)-3-methylbutylcarbamate or {(S)-1-[(S)-1-(1-hydroxy-1-pyridin-2-yl-methyl)-3-phenyl-propylcarbamoyl]-3-methyl-butyl}-carbamic acid benzyl ester; and a compound of Formula I in which A is thiazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is 4-methylpiperazin-1-ylcarbonyl; R2 and R4 each are hydrogen; R3 is phenethyl; and R5 and R6 together form oxo; that is, a compound having the following structure: 
is named N-[3-methyl-1S-(3-phenyl-1-thiazol-2-ylcarbonylpropylcarbamoyl)butyl]-4-methylpiperazine-1-carboxanide or 4-methyl-piperazine-1-carboxylic acid or {(S)-3-methyl-1-[(S)-3-phenyl-1-(1-thiazol-2-yl-methanoyl)-propylcarbamoyl]-butyl}-amide; and a compound of Formula I in which A is 4,5-tetrahydro-4-methoxycarbonyloxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R1 is 2-methylpropyl; R1 is benzyloxycarbonyl; R2 and R4 each are hydrogen; R3 is phenethyl; and R5 and R6 together form oxo; that is, a compound having the following structure: 
is named methyl 2S-(2S-benzyloxycarbonylamino-4-methylvalerylamino)-4-phenylbutyryl-4,5-dihydrooxazole-4-carboxylate or 2-[(S)-2-((S)-2-benzyloxycarbonylamino-4-methyl-pentanoylamino)-4-phenyl-butanoyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester.
Certain compounds of Formula I exist in tautomeric equilibrium. Compounds of Formula I which exist as tautomers are named, illustrated or otherwise described in this application as one possible tautomer. However, it is to be understood that the all possible tautomers are meant to be encompassed by such names, illustrations and descriptions.
Certain compounds of Formulae I and II exist in tautomeric equilibrium. Compounds of Formulae I and II which exist as tautomers are named, illustrated or otherwise described in this application as one possible tautomer. However, it is to be understood that the all possible tautomers are meant to be encompassed by such names, illustrations and descriptions.
Administration and Pharmaceutical Compositions
In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight (xcexcg/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 xcexcg/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 xcexcg/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01% w to 10% w, preferably 0.3% w to 1% w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula: 
wherein X11 is a bond or (C1-7)alkylene, each R43 independently is hydrogen or (C1-30)alkyl, R44 and R45 are selected independently from a group consisting of hydrogen, halo, optionally substituted (C1-30)alkyl, (C3-30)cycloalkyl, hetero(C5-30)cycloalkyl, optionally substituted (C6-10)aryl, hetero(C6-10)aryl, xe2x80x94NR46R46, xe2x80x94OR46, xe2x80x94SR46, wherein each R46 independently is hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, optionally substituted (C6-10)aryl, provided that both R44 and R45 are not selected from hydrogen or hydroxy when X11 is a bond; or R44 and R45 taken together form (C2-9)alkylene; wherein (C3-10)cycloalkyl includes adamantyl and the like, hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.
Instances wherein R44 and/or R45 are substituted (C1-30)alkyl may include, but are not limited to, (C1-30)alkyl substituted by hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C6-10)aryl, xe2x80x94NR47R47, xe2x80x94OR147 and xe2x80x94SR47, wherein each R47 is independently hydrogen or (C1-10)alkyl; wherein hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.
A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy or halo, and R45 is selected from the group consisting of optionally substituted (C1-30)alkyl, halo and xe2x80x94SR46, wherein R46 is (C1-10)alkyl or phenyl.
A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy and chloro and R45 is selected from the group consisting of optionally substituted (C1-30)alkyl, chloro and chlorophenylthio.
A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X11 is a bond, each R43 is hydrogen, R44 is hydroxy and R45 is 3-aminopropyl, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which patents are incorporated by reference herein in their entirety.
Further non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following:
cycloheptylaminomethylene-1,1-bisphosphonic acid (aka cimadronic acid), described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990;
1,1-dichloromethylene-1,1-diphosphonic acid (aka clodronic acid) and the disodium salt thereof, namely clodronate disodium, described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967);
1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid (aka EB-1053);
1-hydroxyethylidene-1,1-diphosphonic acid (aka etidronic acid);
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid (aka ibandronic acid), described in U.S. Pat. No. 4,927,814, issued May 22, 1990;
6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (aka neridronic acid);
3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (aka olpadronic acid);
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (aka pamidronic acid);
2-pyrid-2-ylethylidene-1,1-bisphosphonic acid (aka piridronic acid), described in U.S. Pat. No. 4,761,406;
1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid (aka risedronic acid);
4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989; and
1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (aka zoledronic acid);
all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
A non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. A further non-limiting example is alendronate monosodium trihydrate.
Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-1-ylethoxy)phenyl]methanone (aka raloxifene) and {2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine (aka tamoxifen). A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators. Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-1-ylmethyl)phenyl]acrylamides, described in U.S. Pat. No. 5,985,910 to Miller et al., Nov. 16, 1999; benzothiphene compounds, described in U.S. Pat. No. 5,985,897 to Meuhl et al., Nov. 16, 1999; naphthyl compounds, described in U.S. Pat. No. 5,952,350 to Cullinan et al., Sep. 14, 1999; substituted benzothiophene compounds, described in U.S. Pat. No. 5,962,475 to Schmid et al., Oct. 4, 1999, are suitable estrogen receptor partial agonists for administration with the compounds of Formula I; all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
More particularly a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s). Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiometbylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof and preferably 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.
Chemistry
Processes for Making Compounds of Formula I
Compounds of Formula I in which R5 and R6 together form oxo can be prepared by proceeding as in the following Scheme 1:
in which n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II.
Compounds of Formula I in which R5 and R6 together form oxo (Formula I(a)) can be prepared by reacting an organometallic compound of Formula 2 with a compound of Formula 3. The reaction is carried out in a suitable solvent (e.g. tetrahydrofuran (THF), ether, or the like) at xe2x88x9280 to xe2x88x9270xc2x0 C., preferably at about xe2x88x9278xc2x0 C., and requires 30 minutes to an hour to complete. The organometallic compound of Formula 2 is generated by treating a corresponding organo compound, or a brominated derivative thereof, with n-butyllithium or tert-butyllithium in a suitable solvent (e.g. THF, ether, or the like) at xe2x88x9280 to xe2x88x9270xc2x0 C., preferably at about xe2x88x9278xc2x0 C., for approximately 30 minutes to an hour.
Compounds of Formula I in which the ring comprised by X1 is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, R5 is hydrogen and R6 is hydroxy can be prepared by proceeding as in the following Scheme 2:
in which X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II.
Compounds of Formula I can be prepared by reacting a compound Formula 4 with a compound of the Formula 5(a). The reaction is carried out in a suitable solvent (e.g. chloroform, ethanol, or the like) at reflux temperatures and requires 3 to 24 hours to complete. In a similar fashion, using analogous reaction conditions to those described in Scheme 1, compounds of Formula I in which A is a heteropolycyclic radical wherein X1 is a ring member atom of an oxazole ring, R5 is hydrogen and R6 is hydroxy can be prepared by reacting a compound of Formula 4 with a compound of Formula 5(b): 
in which n is 0, 1, 2 or 3 and B is a heteromonocyclic radical containing 5 to 6 ring member atoms or a fused heteropolycyclic radical containing 8 to 11 ring member atoms, wherein each ring contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom, and R7 and R8 is as defined in the Summary of the Invention for Formulae I and II.
Compounds of Formula I can be prepared by proceeding as in the following Scheme 3: 
in which Y is hydrogen or an activating group (e.g. 2,5-dioxopyrrolidin-1-yl (NBS), or the like) and n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II.
Compounds of Formula I can be prepared by reacting a compound of Formula 6, or a protected derivative thereof, with a compound of the formula R1X2OY, or a protected derivative thereof, and then optionally deprotecting. The reaction is carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, or the like) and in a suitable solvent (e.g. acetonitrile, N,N-dimethylformamide (DMF), dichloromethane, or any suitable combination thereof, or the like) at 10 to 30xc2x0 C., preferably at about 25xc2x0 C., and requires 24 to 30 hours to complete. When Y is hydrogen a suitable coupling agent (e.g. benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP(copyright)), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and base (e.g. N,N-diisopropylethylamine, triethylamine, or the like) is required and the reaction requires 2 to 3 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981. Detailed descriptions of the preparation of a compound of Formula I in accordance with Scheme 3 are set forth in Examples 8, 9, 10 and 12, infra.
Compounds of Formula I can be prepared by proceeding as in the following Scheme 4: 
in which R39 is xe2x80x94X7X8R20 and n, X1, X2, X7, X8, R1, R2, R3, R4, R7, R8 and R20 are as defined in the Summary of the Invention for Formulae I and II.
Additional Processes for Preparing Compounds of Formula I
Compounds of Formula I in which A is optionally substituted oxazol-2-yl can be prepared by oxidizing a corresponding compound of Formula I in which A is 4,5-dihydrooxazol-2-yl. The reduction is carried out in the presence of base (e.g. 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[3.4.0]non-5-ene (DBN), or the like) in a suitable solvent (e.g. dichloromethane, or the like) at 20 to 25xc2x0 C. and requires 6 to 12 hours to complete.
Compounds of Formula I in which R7 is xe2x80x94C(O)OH can be prepared from a corresponding compound of Formula I in which R7 is methoxycarbonyl. The conversion can be effected by treating the methyl ester with sodium hydroxide in a suitable solvent (e.g, ethanol, or the like) at 20 to 25xc2x0 C. and requires 6 to 12 hours to complete.
Compounds of Formula I in which R7 is xe2x80x94C(O)NR29R30 or xe2x80x94C(O)NR42CHR43C(O)OR29, can be prepared by reacting a corresponding compound of Formula I in which R7 is xe2x80x94C(O)OH with a compound of the formula NHR20R21 or NHR42CHR43C(O)OR29, respectively. The reaction is carried out in the presence of a suitable coupling agent (PyBOP(copyright), EDC, HBTU, DCC, or the like) and base (e.g, N,N-diisopropylethylamine, triethylamine, or the like) in a suitable solvent (e.g., DMF, or the like) at 20 to 25xc2x0 C. and requires 2 to 4 hours to complete.
Compounds of Formula I in R1 is xe2x80x94X6X7R20 can be prepared by reacting a compound of Formula I in which R1 is hydrogen with a compound of the formula R20X7X6OH. The reaction is carried out by procedures analogous to those described above for carrying out Reaction Scheme 3.
Compounds of Formula I in which R5 and R6 together form oxo can be prepared by oxidizing a compound of Formula I in which R5 is hydrogen and R6 is hydroxy. The oxidation can be carried out with a suitable oxidizing agent (e.g. Dess-Martin periodinate, or the like) in a suitable solvent (e.g. dichloromethane, or the like) at 15 to 25xc2x0 C. and requires 10 to 20 hours to complete.
Compounds of Formula I in which R12 contains a sulfonyl moiety can be prepared by oxidizing a corresponding compound of Formula I containing a sulfanyl moiety. The oxidation is carried out with a suitable oxidizing agent (e.g. potassium peroxymonosulfate (OXONE(copyright), or the like) in a suitable solvent (e.g. methanol, water, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete.
A compound of Formula I in which A is 1,1-dioxo-1H-1xcex6-benzo[b]thien-2-yl can be prepared by oxidizing a corresponding compound of Formula I in which A is benzo[b]thien-2-yl. Proceeding in this fashion benzyl 1-[1-(1,1-dioxo-1H-1xcex6-benzo[b]thien-2-ylcarbonyl)-3-phenylyropylcarbamoyl]-3-methylbutylcarbamate (Compound 209) was prepared. 1H NMR (CDCl3): xcex4 0.83-0.95 (m, 6H), xcex4 1.35-1.52 (m, 1H), xcex4 1.61-1.69 (m, 2H), xcex4 2.07-2.20 (m, 1H, xcex4 2.36-2.71 (m, 3H), xcex4 4.57 (m, 1H), xcex4 4.76 (m, 1H), xcex4 4.98-5.26 (m, 3H), xcex4 5.35 (bs, 1H), xcex4 7.06-7.62 (m, 14H);
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g. ammonium hydroxide solution, sodium hydroxide, or the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g. hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g. trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g. a halogenated hydrocarbon such as dichloromethane) at approximately 0xc2x0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80xc2x0 C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g. for further details see Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g. 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g. crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g. melting points, boiling points, solubilities, reactivity, and the like) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley and Sons, Inc. (1981).
In summary, an aspect of the invention is a process for preparing a compound of Formula I, which process comprises:
(A) reacting an organometallic compound of Formula 2: 
xe2x80x83with a compound of Formula 3: 
xe2x80x83wherein n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II, to give a compound of Formula I in which R5 and R6 together form oxo; or
(B) reacting a compound of Formula 4: 
xe2x80x83with a compound of Formula 5(a) or 5(b): 
xe2x80x83wherein the dashed line represents an optional bond and B is a monocyclic radical containing 5 to 6 ring member atoms or a fused polycyclic radical containing 8 to 11 ring member atoms, wherein each ring contains 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom and n, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II, to give a compound of Formula I in which the ring comprised by X1 is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or moiety, respectively, R5 is hydrogen and R6 is hydroxy or
(C) reacting a compound of Formula 6:
xe2x80x83with a compound of the formula R1X2OY, wherein Y is hydrogen or an activating group and n, A, X1, X2, R1, R2, R3, R4, R7 and R8 are as defined in the Summary of the Invention for Formulae I and II, to give a compound of Formula I in which R5 is hydrogen and R6 is hydroxy; or
(D) reacting a compound of Formula 7: 
xe2x80x83or a protected derivative thereof, with R39OH, wherein R39 is xe2x80x94X7X8R20 and n, A, X1, X2, X7, X8, R2, R3, R4, R7, R8 and R20 are as defined in the Summary of the Invention for Formulae I and II, and deprotecting if necessary to give a compound of Formula I in which R1 is xe2x80x94X7X8R20,
(E) optionally oxidizing a compound of Formula I in which R5 is hydrogen and R6 is hydroxy to give a compound of Formula I in which R5 and R6 together form oxo;
(F) optionally oxidizing a compound of Formula I in which A is optionally substituted 4,5-dihydroxyoxazol-2-yl to give a compound of Formula I in which A is optionally substituted oxazol-2-yl;
(G) optionally converting a compound of Formula I in which R7 is xe2x80x94C(O)OH to a compound of Formula I in which R7 is methoxycarbonyl;
(H) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(I) optionally converting a salt form of a compound of Formula I to non-salt form;
(J) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(K) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(L) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(M) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Processes for Preparing Intermediates
Compounds of Formula 3 can be prepared by reacting a compound of the Formula 8: 
with a compound of the formula R1X2OY, in which Y is hydrogen or an activating group (NBS, or the like). The reaction is carried out under conditions analogous to those set for Reaction Scheme 3.
Compounds Formula 8 can be prepared by reacting a corresponding amino protected carboxylic acid with N,O-dimethylhydroxylamine hydrochloride and then deprotecting. The reaction with the amine is carried out in the presence of a suitable coupling agent (PyBOP(copyright), EDC, HBTU, DCC, or the like) and base (e.g. N,N-diisopropylethylamine, triethylamine, or the like) in a suitable solvent (e.g. dichloromethane, DMF, or the like) at 20 to 30xc2x0 C., preferably at about 25xc2x0 C., and requires 2 to 4 hours to complete (e.g. see Reference 1, infra.). Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield (e.g. see Example 2, infra.). A detailed description of the preparation of a compound of Formula 8 is set forth in References 1 and 6, infra.
Compounds of Formula 4 can be prepared by reacting a nitrile of Formula 9: 
with ethanol. The reaction is carried out by adding the nitrile to a mixture comprising a catalytic amount of dry hydrogen chloride in a suitable solvent (e.g. chloroform, ethanol, or the like) and then allowing the reaction to proceed at 0 to 25xc2x0 C. for 4 to 6 hours. Dry hydrogen chloride is conveniently generated by combining a slightly excessive amount of ethanol with acetyl chloride prior to adding the imidate to the reaction mixture. Alternatively, the hydrogen chloride is introduced to the reaction medium as a gas.
Compounds of Formula 6 can be prepared by methods known to those of ordinary skill in the art. For example, compounds of Formula 6 in which A is optionally substituted benzooxazol-2-yl can be prepared by reacting a compound of Formula 10: 
in which R40 is a protecting group, with 2-aminophenol and deprotecting. The reaction with the phenol is carried out in the presence of a suitable base (e.g. diisopropylethylamine, triethylamine, or the like) and in a suitable solvent (e.g. chloroform, or the like) at reflux temperatures to 25xc2x0 C. and requires 10 to 12 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the preparation of a compound of Formula 6 is set forth in Reference, infra.
Compounds of Formula 7 can be prepared by condensing a compound of Formula 6 with a compound of the formula R40X2OY, wherein R40 is a protecting group, and then deprotecting. The condensation is carried out in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, or the like) and in a suitable solvent (e.g. acetonitrile, DMF, dichloromethane, or any suitable combination thereof, or the like) at 10 to 30xc2x0 C., preferably at about 25xc2x0 C., and requires 24 to 30 hours to complete. When Y is hydrogen a suitable coupling agent (e.g. PyBOP(copyright), EDC, HBTU, HATU, DCC, or the like) and base (e.g. N,N-diisopropylethylamine, triethylamine, or the like) is required and the reaction requires 2 to 3 hours to complete. Deprotection can be effected by any means which removes the protecting group and gives the desired product in reasonable yield.